Preliminary antitumor activity of BAY 43–9006 in metastatic renal cell carcinoma and other advanced refractory solid tumors in a phase II randomized discontinuation trial (RDT)

Ratain, Mark J.; Flaherty, K. T.; Stadler, Walter M.; O'Dwyer, P.; Kaye, Stan B.; Xiong, Huacai; Patnaik, Amita; Gore, M.; Lee, R. J.; Eisen, Tim

doi:10.1200/jco.2004.22.14_suppl.4501

Cited by 74 publications

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“…Some authors hypothesised that soluble CRP prevents recognition and binding of tumour cells by IL-2-activated effector cells (Kedar et al, 2004). The question arises whether our prognostic and predictive model, established from patients undergoing cytokine treatment, may be relevant in the era of targeted therapies (Ratain, 2004;Yang, 2004;Hainsworth et al, 2005;Motzer et al, 2006). Although these agents have shown promising results in MRCC, it is questionable whether they will completely replace established strategies.…”

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confidence: 99%

Prognostic factors in metastatic renal cell carcinoma: metastasectomy as independent prognostic variable

et al. 2006

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Prognostic and predictive factors in patients with metastatic renal cell carcinoma (MRCC) have been evaluated from untreated patients or patients on several different treatment approaches. The aim of this analysis was to define prognostic and predictive factors in patients treated uniformly with a low-dose outpatient cytokine combination. The relationship between patient-, tumour-, and treatment-related factors was analysed in 99 patients with MRCC. These features were first examined in univariate analyses, then a stepwise modelling approach based on Cox regression was used to form a multivariate model. Nuclear grade, metastasectomyeven incomplete -C-reactive protein and lactate dehydrogenase were identified as independent prognostic factors for survival. Patients assigned to three different risk groups had statistically significant survival differences (30, 22 and 6 months, respectively). A total of 43.4% had undergone metastasectomy, mostly incomplete. Risk group affiliation was correlated with response to treatment. Our findings strongly suggest the consideration of metastasectomy in the management of patients with metastatic renal cell cancer undergoing either immunotherapy or targeted treatment.

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Section: Discussionmentioning

confidence: 99%

Prognostic factors in metastatic renal cell carcinoma: metastasectomy as independent prognostic variable

et al. 2006

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“…Increased signalling through the RAF/MEK/ERK pathway, as a result of autocrine stimulation by basic fibroblast growth factor and hepatocyte growth factor, is implicated in melanocytic tumorigenesis (tumour growth, invasion and metastasis) (Satyamoorthy et al, 2003). Furthermore, the activity of ERK, which is downstream of RAF, has been shown to increase from early-to advanced-stage melanoma (Satyamoorthy et al, 2003).…”

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“…Furthermore, the activity of ERK, which is downstream of RAF, has been shown to increase from early-to advanced-stage melanoma (Satyamoorthy et al, 2003). This increased ERK activity may be the consequence of activating BRAF mutations, which are present in up to 80% of human melanomas Chang et al, 2004;Garnett and Marais, 2004).…”

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“…Sorafenib monotherapy has been shown to have a manageable side effect profile in Phase I/II/III studies (Strumberg et al, 2003Ratain et al, 2004Ratain et al, , 2006Awada et al, 2005;Escudier et al, 2005). The most common toxicities associated with sorafenib are hand-foot skin reaction (HFS), rash and diarrhoea (Strumberg et al, 2003Ratain et al, 2004Ratain et al, , 2006Awada et al, 2005;Escudier et al, 2005).…”

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“…The most common toxicities associated with sorafenib are hand-foot skin reaction (HFS), rash and diarrhoea (Strumberg et al, 2003Ratain et al, 2004Ratain et al, , 2006Awada et al, 2005;Escudier et al, 2005). However, these adverse events are predominantly mild to moderate in severity and easily manageable.…”

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Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis

et al. 2006

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The effects of sorafenib -an oral multikinase inhibitor targeting the tumour and tumour vasculature -were evaluated in patients with advanced melanoma enrolled in a large multidisease Phase II randomised discontinuation trial (RDT). Enrolled patients received a 12-week run-in of sorafenib 400 mg twice daily (b.i.d.). Patients with changes in bi-dimensional tumour measurements o25% from baseline were then randomised to sorafenib or placebo for a further 12 weeks (ie to week 24). Patients with X25% tumour shrinkage after the run-in continued on open-label sorafenib, whereas those with X25% tumour growth discontinued treatment. This analysis focussed on secondary RDT end points: changes in bi-dimensional tumour measurements from baseline after 12 weeks and overall tumour responses (WHO criteria) at week 24, progression-free survival (PFS), safety and biomarkers (BRAF, KRAS and NRAS mutational status). Of 37 melanoma patients treated during the run-in phase, 34 were evaluable for response: one had X25% tumour shrinkage and remained on open-label sorafenib; six (16%) had o25% tumour growth and were randomised (placebo, n ¼ 3; sorafenib, n ¼ 3); and 27 had X25% tumour growth and discontinued. All three randomised sorafenib patients progressed by week 24; one remained on sorafenib for symptomatic relief. All three placebo patients progressed by week-24 and were re-started on sorafenib; one experienced disease re-stabilisation. Overall, the confirmed best responses for each of the 37 melanoma patients who received sorafenib were 19% stable disease (SD) (ie n ¼ 1 open-label; n ¼ 6 randomised), 62% (n ¼ 23) progressive disease (PD) and 19% (n ¼ 7) unevaluable. The overall median PFS was 11 weeks. The six randomised patients with SD had overall PFS values ranging from 16 to 34 weeks. The most common drug-related adverse events were dermatological (eg rash/desquamation, 51%; hand-foot skin reaction, 35%). There was no relationship between V600E BRAF status and disease stability. DNA was extracted from the biopsies of 17/22 patients. Six had V600E-positive tumours (n ¼ 4 had PD; n ¼ 1 had SD; n ¼ 1 unevaluable for response), and 11 had tumours containing wild-type BRAF (n ¼ 9 PD; n ¼ 1 SD; n ¼ 1 unevaluable for response). In conclusion, sorafenib is well tolerated but has little or no antitumour activity in advanced melanoma patients as a single agent at the dose evaluated (400 mg b.i.d.). Ongoing trials in advanced melanoma are evaluating sorafenib combination therapies.

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Treatment of patients with metastatic renal cell cancer

Halbert

Figlin

Atkins

et al. 2006

Cancer

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BACKGROUND.New developments in the treatment of patients with metastatic renal cell cancer (MRCC) have suggested a need to reevaluate the role of systemic therapies. The authors convened a panel of medical and urologic oncologists to rate the appropriateness of the main options.METHODS.The authors used the RAND/University of California‐Los Angeles Appropriateness Method to evaluate systemic therapy options and cytoreductive nephrectomy. After a comprehensive literature review, an expert panel rated the appropriateness of systemic options (108 permutations) and cytoreductive nephrectomy (24 permutations) for patients with MRCC.RESULTS.The appropriateness evaluation indicated that 27.3% of permutations were rated “appropriate,” 46.9% were rated “inappropriate,” and 25.8% were rated “uncertain.” There was a high rate of agreement (95%). Sunitinib and sorafenib were rated appropriate for patients with low‐to‐moderate risk regardless of prior treatment. Temsirolimus was rated appropriate for first‐line therapy for higher risk patients. Interferon‐α and low‐dose interleukin‐2 were rated inappropriate or uncertain. In patients who received prior immunotherapy, cytokines were rated inappropriate. In all permutations for evaluating systemic therapy, enrollment into an investigational trial was considered appropriate, treatment with bevacizumab was uncertain, and thalidomide was inappropriate regardless of risk status or prior therapy. For good surgical risk patients with planned immunotherapy, nephrectomy was rated appropriate in patients who had limited metastatic burden regardless of tumor‐related symptoms and in symptomatic patients regardless of metastatic burden. Only the most favorable combination of surgical risk, metastatic burden, and symptoms generated an “appropriate” rating for patients with planned targeted therapy.CONCLUSIONS.The current results begin the process of defining an appropriate role for cytokines, newer targeted therapies, and surgery in the treatment of MRCC. Cancer 2006. © 2006 American Cancer Society.

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Preliminary antitumor activity of BAY 43–9006 in metastatic renal cell carcinoma and other advanced refractory solid tumors in a phase II randomized discontinuation trial (RDT)

Cited by 74 publications

References 0 publications

Prognostic factors in metastatic renal cell carcinoma: metastasectomy as independent prognostic variable

Prognostic factors in metastatic renal cell carcinoma: metastasectomy as independent prognostic variable

Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis

Treatment of patients with metastatic renal cell cancer

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